Prognostic Value of the Average Lung CT Number in Patients with Acute Paraquat Poisoning

Objective The chest computed tomography (CT) examination is an important clinical examination in the diagnosis and monitoring of paraquat- (PQ-) induced lung injury. The aim of this study was to explore the prognostic value of the average lung CT number acquired by quantitative CT techniques in patients with acute paraquat poisoning in the early stages of the disease. Methods 46 patients who suffered from acute PQ poisoning in the emergency department of the Nanjing Drum Tower Hospital from January 2015 to June 2020 were enrolled in the present study. The patients were divided into survival group (n = 21) and nonsurvival group (n = 25). Clinical data were collected from subjects who met the inclusion criteria, including general information, personal disease history, and laboratory test indicators. The average lung CT numbers of each patient were obtained by quantitative CT techniques. Receiver operating characteristic (ROC) analysis was conducted to assess the prognostic value of average lung CT number in patients with acute paraquat poisoning. Results The average CT numbers of the middle-lung, lower-lung, and whole lung fields in the nonsurvival group were significantly higher than those of the survival group (p < 0.0001). However, the upper-lung field was not significantly different between the two groups (p = 0.7765). The AUCs of different levels ranged from 0.554 to 0.977, among which the lower-lung field presented the largest AUC of 0.977 (95% CI: 0.943∼1; cut-off value: −702Hu; sensitivity 96%; specificity, 90.5%; YI: 0.865), followed by the whole lung field 0.914 (95% CI: 0.830∼0.999; cut-off value: −727Hu; sensitivity 76%; specificity, 95.2%; YI: 0.712) and the middle-lung field 0.87 (95% CI: 0.768∼0.971; cut-off value: −779Hu; sensitivity 80%; specificity, 85.7%; YI: 0.657). Conclusion The present study indicated that the average lung CT number could be used to evaluate the relationship between the severity of PQ-induced lung injury and prognosis, especially in the lower-lung field. However, further research is needed to draw a clear conclusion.


Introduction
Paraquat (PQ) is a widely used herbicide in agriculture.Despite its frequent use, it is highly toxic to both humans and animals [1].Although certain Asian countries have implemented strategies to strictly control its sales and use, PQ poisoning incidents occur frequently, and the overall mortality rate is estimated to be higher than 50%, mainly due to the intrinsic toxicity of this compound and the lack of efective treatment methods [2].Te lethal dose in adults is very low.Specifcally, only 5-15 ml 20% PQ aqueous solution can be lethal [3].Following its absorption through the gastrointestinal tract, the plasma concentration of PQ reaches maximum levels from 0.5 to 4 h.During that period, this compound is rapidly distributed to the lungs, kidneys, liver, muscles, and other tissues, causing damage.Te main target organ involved is the lung, in which the concentration of PQ is 10-90 times higher than that noted in plasma [4,5].
Although several basic research and clinical research studies have been performed on PQ poisoning, the results have not been summarized by international guidelines regarding the prevention of this disease [6].Regrettably, there is no specifc antidote available and the patients are mainly treated with supportive treatment.For patients with severe poisoning, it is difcult to improve the prognosis even with various treatment methods, while for some patients with mild poisoning, reasonable management and treatment can obtain a good prognosis.Tus, the early prediction of the severity of acute PQ poisoning can aid the guidance of appropriate treatment.Current studies on the prognosis of paraquat poisoning mainly include the amount of paraquat ingested [7], hematological indicators [8][9][10], biological indicators [11][12][13], various rating scales [14,15], and ultrasound and imaging indicators [16,17].However, no unifed clinical standards are present for prognostic evaluation of PQ poisoning to date.Clinicians usually judge the severity of the disease according to the amount of paraquat ingested, the concentration of PQ in blood or urine, and other clinical examination fndings.Besides, these markers have not been widely used in the majority of hospitals due to the requirement for specialized and expensive equipment.In addition, the clinical judgment of the intake dose of PQ poisoning is easily afected by factors, such as the patient's self-description, vomiting, gastric lavage, PQ dosage form, and other factors.It is often difcult for doctors to assess the progression of the disease based on the poisoning dose described by the patient.
Chest CT is an important method for the clinical diagnosis and monitoring of PQ-induced lung injury and has become a routine examination of PQ poisoning in hospitalized patients [18].Numerous studies [17,[19][20][21] have demonstrated that chest CT is also of high value in the prognosis of PQ poisoning, while the optimal indicator remains unclear.Computed tomography (CT) number, also known as the Hounsfeld Unit, is a relative quantitative measurement of x-ray density [22].It is the most frequently used quantitative CT parameter and widely used in radiological diagnosis, attenuation correction, and radiotherapy treatment planning [23].However, there are few clinical studies on the efect of the average lung CT number on the prognosis of acute PQ poisoning patients.Terefore, the purpose of this study was to analyze the predictive impact of the average lung CT number on the prognosis of acute PQ poisoning patients in order to explore whether it can be used as a prognostic index in acute PQ poisoning patients.

Methods and Materials
2.1.General Information.Te present retrospective analysis collected medical records of patients diagnosed with PQ poisoning from January 2015 to June 2020.Te patient screening process is shown in Figure 1.Finally, 46 patients were included in the study (Table S1).According to the disease prognosis, the patients were divided into survival group (n = 21) and nonsurvival group (n = 25).

Patients Management and Outcomes
Based on the experience obtained from the local diagnostic and treatment team and from previously published studies [2,3], all enrolled patients received a corresponding therapeutic regimen during their hospitalization, including gastric lavage, hemoperfusion, hemofltration, glucocorticoids, immunosuppressants, antioxidants, anti-infectives, and other symptomatic support medications.Data supplement presents the protocol for PQ detoxifcation.

Research Methods.
Te initial clinical baseline data of all patients were collected, including gender, age, mode of poisoning, oral dose of poisoning, time from poisoning to medical treatment, time from admission to chest CT examination, time from poisoning to chest CT examination, hospital length of stay, body temperature, pulse rate, respiratory rate, mean arterial pressure, fnger pulse oxygen, smoking history, drinking history, and plasma concentration of paraquat.
Te chest CT images of the patients on admission were collected.Chest CT examination of patients with acute PQ poisoning was routinely performed using the Philips ICT apparatus (128 rows) with a scanning layer thickness of 1-2 mm.Te imaging data were analyzed using the Neusoftpicture archiving and communication system (PACS) (VE 5.5).Te three standard levels of chest HRCT were 2 Emergency Medicine International defned as follows: carinal plane, 5 cm plane above the carina, and 5 cm plane below the carina (Figure 2) [24][25][26].Te average CT numbers of the three levels represent the mean lung density of the upper-, middle-, and lower-lung felds, respectively.Te average CT number of the whole lung was defned as the average of three standard level measurements.Te measurement tools in the PACS system were used to select the largest lung feld area as far as possible, also known as the region of interests (ROIs).Subsequently, the average CT numbers (window level, −600 HU; window width, 1,600 HU) of the ROIs were calculated automatically.Te same standard level was measured twice, and the average of the two measurements was obtained as the average CT number of the level.

Statistical Analysis.
All analyses were conducted using SPSS version 22 (SPSS Inc., Chicago, IL, USA).Te analysis of the measurement data was performed using an independent sample t-test.Te analyzed data are presented as mean ± standard deviation.Te count data are expressed as a number of cases (percentage), and the comparison between the groups was performed by the χ 2 test.Te ROC curves were computed, and the areas under the curves (AUCs) were used to study the discriminatory power of the lung average CT number regarding mortality.Te parameters sensitivity, specifcity, Youden index (YI), and cut-of value (sensitivity + specifcity-1) of the various predictors were also calculated to provide a complete description of the prediction parameters.A two-tailed p < 0.05 was considered to indicate a statistically signifcant diference.

Baseline Characteristics.
Te present study enrolled 98 patients with acute PQ poisoning, of whom 52 did not meet the eligibility criteria and were excluded (Figure 2).1).

Comparison of the Average CT Number between Two
Groups.Te average CT numbers of the middle-lung, lowerlung and whole lung felds in the nonsurvival group were signifcantly higher than those of the survival group (p < 0.0001).However, the upper-lung feld was not signifcantly diferent between the two groups (p � 0.7765) (Table 2).

Discussion
Acute PQ poisoning can cause multiple organ dysfunctions, such as lung injury, acute kidney injury (AKI), and liver dysfunction.Although the morbidity rate of this disease has decreased compared with previous years, its mortality rate remains high [6].Patients with acute PQ poisoning are vulnerable and exhibit a low healing rate.Although the measurement of blood or urine PQ concentration is currently a reliable predictor, it is not easily available in all hospitals.In clinical practice, it is also difcult for doctors to accurately determine the dose of poison (Table S1).So far, the evaluation criteria for the prognosis of acute PQ poisoning have not yet been clinically unifed.In the present study, the relationship between the average lung CT number and the prognosis in the early stage of PQ poisoning was explored.Our results indicated that the average lung CT numbers in the lower-lung, middle-lung, and whole lung felds were signifcantly diferent between the survival group and the nonsurvival group.By using further analysis, it was shown that the average lung CT number was a good predictor of mortality in patients with acute PQ poisoning, especially in the lower-lung feld.
Lung injury caused by PQ is one of the most common clinical manifestations of this condition.Te mechanism of lung injury caused by PQ has not yet been fully elucidated and mainly includes acute infammatory responses, free radical production, oxidative stress, lipid peroxidation, abnormal gene response, and activation of various signaling pathways [2,[27][28][29].PQ-induced lung injury is a dynamic process of pathological evolution [20].In 1991, Im et al. [30] retrospectively analyzed the characteristics of chest CT changes in 45 patients with acute PQ poisoning and confrmed this dynamic evolutionary process.Similar results were noted in a rat model of acute PQ poisoning [31].Chest CT examination, notably high-resolution CT, is an important method to diagnose and monitor PQ-induced lung injury and has been widely used in hospitals.Lung CT Emergency Medicine International fndings can be used as a prognostic indicator for patients with lung injury caused by acute PQ poisoning.In 1994, Lee et al. [20] demonstrated that ground glass changes on chest imaging exhibited prognostic value in patients with acute PQ poisoning.Zhang et al. [17] compared the chest CT fndings of 78 patients with acute PQ poisoning following admission and 3 days following treatment.Te results indicated that the patients in the death group exhibited a higher number of lung lesions and a higher incidence of exudation, consolidation, and fbrosis compared with those of the survival group.Te conduct of multiple chest CT examinations during treatment can assess the evolution of lung injury in a timely fashion and provide important information for improving clinical treatment.However, the evaluation indicators and clinical criteria of chest CT in patients with acute early-stage PQ poisoning remain to be improved.Kang et al. [32] quantitatively analyzed the lungs of 97 cases of PQ poisoning within 5 days, and the results indicated that the ground-glass opacity volume ratio could be used as a new, reliable, and independent indicator for predicting the outcome of acute PQ poisoning.Tis index was superior to the estimated PQ intake, blood or urine PQ concentration, Acute Physiology and Chronic Health Evaluation II (APACHE-II), and Sequential Organ Failure Assessment Score (SOFA).Te optimal cut-of value of the GGO volume ratio was 10.8%, while the sensitivity and specifcity were 85.4% and 89.3%, respectively.Liu et al. [33] prospectively evaluated the prognostic roles of quantitative CT and pulmonary function tests and the association of dynamic strain and ventilation heterogeneity during unassisted   ) and the percentage of residual volume/total lung capacity were independent prognostic indicators.In addition, higher dynamic strain and increased ventilation heterogeneity during unassisted spontaneous breathing were associated with reduced survival independent of these two indicators, which suggested that the role of lung strain changes could not be ignored in disease prognosis following PQ poisoning.Furthermore, Liu et al. [34] proposed that the ratio of damaged lung volume fraction could also be used to evaluate the prognosis of acute PQ poisoning by combining the region growing segmentation method and an artifcial neural network.However, the clinical operability was not appropriate.
In the present study, the prognostic value of the average lung CT number was evaluated in patients with acute PQ poisoning.Te data indicated that the diagnostic power of the average CT number in lower-lung, middle-lung, and whole lung felds were superior to that of the plasma PQ concentration, which was a univariate predictor of the prognosis of patients with acute PQ poisoning.It is worth noting that the average lung CT numbers in diferent levels consist with the lung injury.Te average CT number in the lower-lung feld was higher than the middle-and upper-lung felds no matter in the nonsurvival group and the survival group, which was probably attributed to the gravitational force.
Te present study contains several limitations.First, our sample size was small, mainly due to the government's strict control over the sales policy and the use of PQ.Second, only 3 representative levels were selected for the present study, which could not completely simulate the changes in the average whole lung CT number.Finally, we did not evaluate the association between a dynamic change in the average CT number and the prognosis of patients with acute PQ poisoning.

Conclusion
In the present study, we demonstrated that the average lung CT number was an optimal early predictor of mortality in patients with acute PQ poisoning, especially in the lowerlung feld.However, further research is required to confrm this fnding.

Figure 1 :
Figure 1: Flow chart indicating enrolment and status of patients.

Figure 3 :
Figure 3: Comparison of receiver operating characteristics curves of the middle-lung feld, lower-lung feld, whole lung and the plasma concentration of PQ for predicting the outcome of acute PQ poisoning.
Te fnal analysis included 46 patients, of whom 25 comprised the nonsurvival group (12 males/13 females; mean age 44.68 ± 17.026 years) and 21 the survival group (10 males/11 females; mean age 40.52 ± 14.327 years).No diferences were noted in age, sex ratio, mode of poisoning, time from poisoning to treatment, time from admission to chest CT examination, time from poisoning to chest CT examination, hospital length of stay, body temperature, respiratory rate, heart rate, respiratory rate, mean arterial pressure and fnger pulse oxygen, rate of smokers, and rate of drinkers between the survivor and nonsurvival groups (all p > 0.05).It is expected that the toxic dose described by the patients correlated with the plasma concentration of PQ.Te diferences were statistically signifcant between the two groups (p < 0.01) (Table

Table 1 :
Comparisons of baseline characteristics between the survival and nonsurvival groups with acute PQ poisoning.Two patients in the nonsurvival group had both a history of smoking and drinking, while one patient had a history of both smoking and drinking in the survival group.† Plasma concentration of paraquat was detected by high performance liquid chromatography (HPLC). *

Table 2 :
Comparison of lung average CT number at diferent levels between the survival and nonsurvival groups with acute PQ poisoning (x ± s).

Table 3 :
Predictive value of various indicators for the prognosis of patients with acute PQ poisoning.